A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study

Abstract

Aims To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. Methods and results Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43–3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20–80%) PRS. Conclusion The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility. Key question Key finding Take-home message The incorporation of polygenic risk into clinical care setting may provide a valuable risk stratification guidance to identify high-risk individuals for targeted intervention in primary prevention of CAD.

Genetic Predisposition, Fruit Intake and Incident Stroke: A Prospective Chinese Cohort Study

“…The study design and methods of the China-PAR project have been reported in detail, previously [ 16 , 17 ]. The study included three prospective cohorts with dietary records that were part of the China-PAR project, comprising the China Multi-Center Collaborative Study of Cardiovascular Epidemiology (China MUCA-1998), the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA), and the Community Intervention of Metabolic Syndrome in China and Chinese Family Health Study (CIMIC).…”

Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association

“…23,38,63,89,94 This enhanced prediction is independent of conventional clinical risk factors (Figure 3), is detectable before the emergence of clinical risk factors, and is appreciable across a spectrum of ages, sexes, and, increasingly, ancestries and ethnicities (South Asian, Black/African American/Black Caribbean/Black African, Chinese, and Japanese). 23,36,38,63,84,94,102,103 The inclusion of PRS in the AHA/ACC ASCVD risk calculator significantly improves prediction, and early evidence suggests that targeted screening may be cost-effective (further discussed in the Considerations for Payers section), 104 particularly because evidence suggests that conventional tools are missing participants at high PRS risk. 89…”

Impact of cardiovascular health and genetic risk on coronary artery disease in Chinese adults

“…Genetic variants displaying genome-wide significant associations (p<5×10 −8 ) with CAD or CAD-related traits (stroke, BP, lipids, diabetes and obesity) were selected 14. Individuals were genotyped using multiplex PCR targeted amplicon sequencing technology with Illumina Hiseq X Ten sequencer.…”

“…After excluding those with genotyping miss rate of >5% or sequencing depth of <30×, 540 genetic variants were used to construct trait-specific PRSs and integrated to a combined PRS with the elastic-net regression (variants included were shown in online supplemental table 1). The PRS showed good performance, with the C-index of 0.728 in the age-adjusted and sex-adjusted model 14. We stratified the PRS into low (bottom quintile), intermediate (two to four quintiles) and high (top quintile) categories by quintiles.…”

“…Effects of genetic variants associated with CAD and CAD-related traits from genome-wide association studies translated into the Polygenic Risk Scores (PRSs), which were primarily evaluated in Europeans 9–13. Recently, we have developed and validated a CAD PRS with power in risk prediction and stratification in Chinese 14 15. Evidence from Europeans reported that lifestyles and genetics were independently associated with incident CAD and a healthy lifestyle reduced CAD risk regardless of genetic risk 9 10 16–18.…”